Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)

NCT ID: NCT01339910

Last Updated: 2023-01-04

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 272 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2017-10-16

Brief Summary

The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.

Detailed Description

Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m^2) and melphalan (less than 150 mg/m^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.

Conditions

Leukemia, Myelocytic, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Reduced Intensity Conditioning (RIC)

One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.

Group Type: EXPERIMENTAL

Fludarabine and Busulfan

Intervention Type: DRUG

(Flu/Bu)

• Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2)
• Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4

Fludarabine and Melphalan

Intervention Type: DRUG

(Flu/Mel)

• Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2)
• Melphalan: 140 mg/m^2 on Day -2

Myeloablative Conditioning Regimen (MAC)

One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation.

Group Type: ACTIVE_COMPARATOR

Busulfan and Fludarabine

Intervention Type: DRUG

(Bu/Flu)

• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2
• Fludarabine: 30 mg/m^2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2)

Busulfan and Cyclophosphamide

Intervention Type: DRUG

(Bu/Cy)

• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4
• Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Cyclophosphamide and Total Body Irradiation

Intervention Type: DRUG

(Cy/TBI)

• TBI: 1200-1420 cGy on Days -7 to -4
• Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Interventions

Fludarabine and Busulfan

(Flu/Bu)

• Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2)
• Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4

Intervention Type: DRUG

Fludarabine and Melphalan

(Flu/Mel)

• Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2)
• Melphalan: 140 mg/m^2 on Day -2

Intervention Type: DRUG

Busulfan and Fludarabine

(Bu/Flu)

• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2
• Fludarabine: 30 mg/m^2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2)

Intervention Type: DRUG

Busulfan and Cyclophosphamide

(Bu/Cy)

• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4
• Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Intervention Type: DRUG

Cyclophosphamide and Total Body Irradiation

(Cy/TBI)

• TBI: 1200-1420 cGy on Days -7 to -4
• Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Intervention Type: DRUG

Other Intervention Names

Fludara and Busulfex; Fludara and Alkeran; Busulfex and Fludara; Busulfex and Cytoxan; Cytoxan and radiation

Eligibility Criteria

Inclusion Criteria

• Age equal or less than 65 years old and equal to or greater than 18 years old.
• Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen enrollment.
• For patients receiving treatment of their MDS or AML prior to transplantation: a)Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b)Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days.
• Patients must have a related or unrelated bone marrow or peripheral blood donor who is human leukocyte antigen (HLA)-matched at 7 or 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
• HCT-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4.
• Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40%; b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 times the upper limit of normal.; c)Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) greater than or equal to 40% and forced expiratory volume in one second (FEV1) greater than or equal to 50% (corrected for hemoglobin).
• Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula.
• Signed informed consent.

Exclusion Criteria

• Prior allograft or prior autograft.
• Symptomatic coronary artery disease.
• Leukemia involvement in the central nervous system (CNS) within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
• Karnofsky Performance Score less than 70.
• Patients receiving supplemental oxygen.
• Planned use of donor lymphocyte infusion (DLI) therapy.
• Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms).
• Patients seropositive for the human immunodeficiency virus (HIV).
• Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
• Females who are pregnant or breastfeeding.
• Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

Mayo Clinic Phoenix

Phoenix, Arizona, United States

University of California, San Diego Medical Center

La Jolla, California, United States

University of Florida College of Medicine

Gainesville, Florida, United States

Florida Hospital Cancer Institute

Orlando, Florida, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

Blood and Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States

University of Kansas

Kansas City, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

DFCI, Brigham & Women's Hospital

Boston, Massachusetts, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University/Barnes Jewish Hospital

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Mount Sinai Medical Center

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

University of North Carolina Hospital at Chapel Hill

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Jewish Hospital BMT Program

Cincinnati, Ohio, United States

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

Baylor University Medical Center

Dallas, Texas, United States

Texas Transplant Institute

San Antonio, Texas, United States

Utah BMT/University of Utah Medical School

Salt Lake City, Utah, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

West Virginia University Hospital

Morgantown, West Virginia, United States

University of Wisconsin Hospital & Clinics

Madison, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51. doi: 10.1182/blood-2009-03-209262. Epub 2009 Apr 8.

Reference Type: BACKGROUND

PMID: 19357394 (View on PubMed)

Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005 Oct 15;106(8):2912-9. doi: 10.1182/blood-2005-05-2004. Epub 2005 Jun 30.

Reference Type: BACKGROUND

PMID: 15994282 (View on PubMed)

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.

Reference Type: BACKGROUND

PMID: 16338616 (View on PubMed)

Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, Wagner JE, Yanovich S, Kernan NA. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007 Dec;13(12):1469-76. doi: 10.1016/j.bbmt.2007.08.047.

Reference Type: BACKGROUND

PMID: 18022577 (View on PubMed)

Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. doi: 10.1200/JCO.2016.70.7091. Epub 2017 Feb 13.

Reference Type: RESULT

PMID: 28380315 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Informed Consent Form

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U01HL069294

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01HL069294-05

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 0901

Identifier Type: OTHER

Identifier Source: secondary_id

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN0901

Identifier Type: -

Identifier Source: org_study_id